PROJECT SUMMARY How functionally flexible is human cortex? The current proposal approaches this question by studying visual cortex plasticity in blindness. In individuals who are blind from birth, so-called ?visual? cortices respond to touch and sound. How similar are these new functions to the original visual computations? A longstanding view is that functional reorganization is limited, even in cases of plasticity. Our recent published work and preliminary data, however, suggest that functional reorganization in the visual cortices of blind individuals may be more radical than previously thought. We find that regions within retinotopic visual cortices are active during language and math tasks, and that this activity is sensitive to the grammatical structure of sentences and the difficulty of math equations. Such functional repurposing is striking, in light of the cognitive and evolutionary differences between vision, language and mathematics. These new findings offer an unprecedented opportunity to test the limits of human cortical flexibility. In this proposal we test the hypothesis that human cortex is functionally pluripotent: capable of assuming a wide range of cognitive functions depending on input, where input is determined by experience and connectivity. We hypothesize that language-related plasticity in visual cortices is part of a broader phenomenon whereby, in blindness, visual cortices are colonized by multiple distinct higher-cognitive functions as a result of strong connectivity between visual cortex and higher-cognitive networks, and fronto-parietal networks in particular. Up until now there has been little evidence for specialization within visual cortices of blind individuals. Aim 1 tests the prediction that in individuals who are blind from birth different regions within visual cortices are specialized for: language, number, and cognitive control and that specialization is related to connectivity with different fronto-parietal networks. In the first part of Aim 2, we use multi-voxel pattern analysis and fMRI adaptation to test the prediction that visual cortices of blind individuals represent higher-cognitive information, such as the meanings of words and numerical quantity. Next we test the prediction that visual cortices are functionally relevant to higher-cognitive behavior using transcranial magnetic stimulation (TMS). Aim 3 examines the time-course of visual cortex plasticity during the lifespan. By working with individuals who lost their sight at different ages we test the hypothesis that cortex assumes higher-cognitive functions only during a sensitive period of development. This work is highly relevant to understanding the pathophysiology of visual impairments and uncovering the timing and mechanisms by which blindness affects the human brain. The insights about plasticity to be gained from the proposed project have far-reaching relevance for optimizing cortical function in the context of neurological and cognitive disabilities.